A nuclear factor κB (NF-κB) is a transcription factor that regulates the expression of genes responsible for reactions involved in the survival of an organism. Examples of known genes whose expression is regulated by this NF-κB include genes of many inflammatory factors including inflammatory cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-1, and IL-6, cyclooxygenase-2 (COX-2), inducible NO synthetase (iNOS), and cell adhesion molecules such as ICAM and VCAM.
Meanwhile, many stimuli that induce the activation of NF-κB are also known and examples thereof include stimuli such as inflammatory cytokines such as IL-1 and TNF-α, bacterial cell products such as bacterial lipopolysaccharides (LPS), viruses, various stresses such as ultraviolet light and γ-ray irradiation, and T-cell mitogens.
NF-κB is thought to be involved in many conditions associated with inflammation, including rheumatoid arthritis (Non-patent Document 1), angiogenesis (Non-patent Document 2), arteriosclerosis (Non-patent Document 3), endotoxin shock and sepsis (Non-patent Document 4), inflammatory bowel disease (Non-patent Document 5), ischemic reperfusion injury (Non-patent Document 6), and pneumonia (Non-patent Document 7). Furthermore, previous studies have shown that NF-κB plays an important role in etiology and development of cancer (Non-patent Document 8).
In a cell with no stimulus, NF-κB binds to IκB, an inhibitory protein, to form a complex and exists in cytoplasm. This complex formation confines NF-κB in cytoplasm, inhibiting transfer thereof to the nucleus. When the cell is stimulated, specific amino acid residues of IκB (serine residues 32 and 36 in the case of IκBα) is phosphorylated, further polyubiquitinated, and degraded by proteasomes (Non-patent Document 9). NF-κB released from IκB rapidly transfers into the nucleus and activates the transcription of a target gene.
IκB is phosphorylated by IκB kinase (IKK). IKK is a kinase complex having catalytic subunits known as IKKα (also referred to as IKK1) and IKKβ (also referred to as IKK2) (Non-patent Documents 10 and 11). IKK is activated by phosphorylation, and MEKK1, MEKK3, NF-κB inducing kinase (NIK), and the like are known as phosphorylases thereof.
The view is advocated that inhibition of NF-κB activation by allowing IκB to exist stably is effective measure for the treatment of autoimmune diseases and other diseases. For example, when IκB is overexpressed in Synovial membrane cells collected from a patient with rheumatoid arthritis, the expression of TNF-α, IL-6, and IL-8 decreased (Non-patent Document 12). Furthermore, a transgenic mouse that expresses proteolysis-resistant IκB in T cells showed resistance to collagen-induced arthritis (Non-patent Document 13).
It has been reported that inhibition of phosphorylation of IκB by IKK is effective for the stabilization of IκB (Non-patent Document 14). NF-κB is activated by inflammatory cytokines in synovial membrane cells derived from a patient with rheumatoid arthritis. However, when NF-κB is expressed in synovial membrane cells deficient in the IKKβ kinase activity, IκB stably exists even with stimuli of inflammatory cytokines and then activation of NF-κB is suppressed. This suggests that the kinase activity of IKKβ plays a central role in activation of NF-κB (Non-patent Document 14).
Therefore, suppression of NF-κB activation by inhibiting the IKK activity may be effective for the treatment of autoimmune diseases, inflammatory diseases, cardiovascular diseases, and cancer.
β-carboline derivatives (Patent Document 1), aminothiophene derivatives (Patent Document 2), imidazole derivatives (Patent Document 3), indole derivatives (Patent Document 4), aminopyridine derivatives (Patent Document 5), anilinophenylpyrimidine derivatives (Patent Document 6), pyrazolaquinazoline derivatives (Patent Document 7), and indazole derivatives (Patent Document 8) are disclosed as examples of compounds inhibiting the IKK activity.